Regulation of Membrane Associated Fatty Acid Transporter Expression

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Extensive studies examining the effect of diet on the levels of putative membrane transporters have not yet been published. Studies employing whole animal models, however, have provided some information regarding overall regulation of these proteins. For example, FABPpm expression is markedly elevated in the white adipose tissue of Zucker diabetic and obese (fa/fa) rats.62 These rats have lost insulin sensitivity and therefore an increased level of FABPpm mRNA in these animals indicates insulin is a negative regulator of FABPpm expression. The insulin effect in these animals appears to be tissue sensitive, as there was no difference in FABPpm levels in the liver of these rats.62 No information regarding the presence or absence of an insulin-responsive element (IRE) upstream of the FABPpm coding region is available to date. FABPpm levels are also affected by the FA utilization requirements of the tissue. FABPpm levels have been shown to increase in oxidative skeletal muscle during fasting, a metabolic state that necessitates high FA utiliza-tion.63 In addition, studies in humans have demonstrated that the protein is induced in skeletal muscle with prolonged endurance training, again concomitant with an increased need for FA utilization.64-66

Similar to FABPpm, FATP mRNA levels can also be increased markedly by nutrient depletion. This marked increase was observed in murine adipose tissue and has been attributed to an insulin effect at the level of transcription, with insulin downregulating FATP mRNA.67 An insulin-responsive element (IRE) for FATP has been identified, and is similar to other known insulin-responsive regulatory sequences.67,68 In accordance with the presence of an insulin-control element, FATP expression is elevated in the adipose tissue of the insulin-resistant Zucker diabetic and obese fa/fa rats.62 FATP expression is also under the control of peroxisome proliferating agents, which include fatty acids, and will be discussed below.

FAT/CD36 expression is also altered in a diabetic state. For example, CD36 protein levels are increased several-fold in NOD diabetic mice69 and CD36 mRNA levels are slightly elevated in the Zucker diabetic and obese rats, although not to the extent that the FABPpm and FATP mRNA levels are increased.62 Further clarification of the regulatory relationship between FAT/CD36 expression and insulin is required.19 The distribution of FAT mRNA along the gastro-colic axis is greatest in the jejunum, the main site of fatty acid absorption, and its mRNA levels are regulated by the intake of dietary fat. Specifically, high fat diets administered to rats increase FAT mRNA levels, with a diet rich in long-chain fatty acids increasing levels most dramatically.70 The effect of dietary fats may be due directly to the action of a series of fatty acid-responsive nuclear receptors. Indeed, both fatty acids and other lipophilic compounds such as peroxisome proliferators induce FAT mRNA expression,71,72 and the gene appears to be regulated directly by these ligands, as will be discussed below.

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